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Zinc signals are utilized by several immune cell receptors. One is TLR4, which causes an increase of free zinc ions (Zn(2+)) that is required for the MyD88-dependent expression of inflammatory cytokines. This study investigates the role of Zn(2+) on Toll/IL-1R domain-containing adapter inducing IFN-β (TRIF)-dependent signals, the other major intracellular pathway activated by TLR4. Chelation of Zn(2+) with the membrane-permeable chelator N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine augmented TLR4-mediated production of IFN-β and subsequent synthesis of inducible NO synthase and production of NO. The effect is based on Zn(2+) acting as a negative regulator of the TRIF pathway via reducing IFN regulatory factor 3 activation. This was also observed with TLR3, the only TLR that signals exclusively via TRIF, but not MyD88, and does not trigger a zinc signal. In contrast, IFN-γ-induced NO production was unaffected by N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine. Taken together, Zn(2+) is specifically involved in TLR signaling, where it differentially regulates MyD88 and TRIF signaling via a zinc signal or via basal Zn(2+) levels, respectively.
Brieger et al. (Thu,) studied this question.